1. Field of the Invention
The present invention generally relates to processes for the synthesis of drospirenone.
2. Description of the Relevant Art
Drospirenone is a synthetic steroid with progestin, anti-mineral corticoid and anti androgen activity. Drospirenone is currently being used as a synthetic progestin in oral contraceptive formulations. A regioselective synthesis for drospirenone has been described (see e.g., Angew. Chem. 94, 1982, 718) that uses the 17 keto derivative (1) as a key intermediate.

The synthesis of intermediate (1) and the transformation of intermediate (1) into drospirenone has been described in, for example, U.S. Published Patent Application Nos. 2009/0023914; 20080207575; 2008/0200668; 2008/0076915, 20070049747, and 20050192450; U.S. Pat. Nos. 6,933,395; 6,121,465, and 4,129,564, European Patent No. 0 075 189 and PCT Publication No. WO 2006/061309, all of which are incorporated herein by reference. Many of these routes introduce the required C3 side chain in the 17 position of intermediate (1). These conversions are usually carried out with carbanions, such as propargylalcohol, trimethylsulfoxonium iodide, or the use of the anion generated from a suitably protected derivative of 1-bromopropionaldehyde. After oxidation of the 3-hydroxy substituent to a 3-keto group, and the oxidative formation of the 17-spirolactone, the 3-keto-5-hydroxy-17-spirolactone is transformed via acid catalysis into drospireneone. If the oxidation is performed under acidic conditions at elevated temperatures, the oxidation and elimination can be run without isolation of the intermediate products.
Most of these procedures rely on the acid-catalyzed elimination of the 5-hydroxy group in the last step of the synthesis. It has been documented that 15,16-methylene-17-spirolactones are prone to undergo rearrangement to generate the inverted 17-spirolactone under mild acidic conditions (see, for example, Tetrahedron Letters, Vol. 27, No 45, 5463-5466) in considerable amounts. This isomer has very similar physical chemical properties, and typically requires chromatographic separation or repeated fractional recrystallizations to purify the product. This isomerization can make these approaches less desirable from an economical point of view.
For the above given arguments, a process that avoids the acidic treatment of intermediates containing the 15,16-methylene-17-spirolactone could offer a significant advantage because of the avoidance of the generation of the undesired 17-spirolactone isomer.